Nanotechnology Approaches to Targeting Inflammation and Excitotoxicity in a Canine Model of Hypothermic Circulatory Arrest-Induced Brain Injury.
Nanotechnology Approaches to Targeting Inflammation and Excitotoxicity in a Canine Model of Hypothermic Circulatory Arrest-Induced Brain Injury.
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DOI：
10.1016/j.athoracsur.2016.02.077
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发表时间：
2016-09
期刊：
影响因子：
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通讯作者：
Baumgartner WA
中科院分区：
文献类型：
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作者：
Grimm JC;Magruder JT;Wilson MA;Blue ME;Crawford TC;Troncoso JC;Zhang F;Kannan S;Sciortino CM;Johnston MV;Kannan RM;Baumgartner WA
神经认知功能障碍和损伤在需要低温停循环（HCA）的心脏手术后仍然是个问题。由于与全身药物治疗相关的血脑屏障（BBB）渗透率和毒性差，临床成功一直是难以捉摸的。因此，我们在我们完善的HCA犬模型中探索了靶向树枝状聚合物（纳米颗粒）-药物疗法，以表征这些纳米颗粒在已知神经元凋亡和坏死区域中的生物分布和细胞定位。对A类27-30 kg雄性猎犬给予初始静脉内推注[总剂量（200 mg）的10%] Cy 5标记的树枝状聚合物（D 6-Cy 5，6.7-nm），并通过外周插管进行心肺转流。在90分钟的HCA后，在6小时内输注总剂量的70%。最后20%的总剂量在HCA后24小时给予。48小时后（HCA后72小时），收获脑并分析D 6-Cy 5生物分布。背侧海马表现出D 6-Cy 5的最高脑积累，这与组织学染色和共聚焦成像上明显的凋亡神经元的分布密切对应。在受损的脑区域中，树枝状聚合物穿过BBB并定位在靶细胞（受损的神经元和小胶质细胞）内。这是第一个已知的研究，以说明一致的神经元/小胶质细胞摄取的树枝状聚合物药物输送系统在一个大型动物模型后，全身给药。这些发现对未来开发新的治疗方法以减轻这组患者的神经认知缺陷具有令人兴奋的意义。
Neurocognitive dysfunction and injury remain problematic following cardiac procedures requiring hypothermic circulatory arrest (HCA). Due to poor blood-brain-barrier (BBB) penetrance and toxicities associated with systemic drug therapies, clinical success has been elusive. Accordingly, we explored targeted dendrimer (a nanoparticle)-drug therapies in our well established canine model of HCA to characterize the biodistribution and cellular localization of these nanoparticles in areas of known neuronal apoptosis and necrosis. Class-A, 27-30 kg male hounds were administered an initial intravenous bolus [10% of the total dose (200mg)] of Cy5-labeled dendrimer (D6-Cy5, 6.7-nm) and placed on cardiopulmonary bypass via peripheral cannulation. After a 90-minute period of HCA, 70% of the total dose was infused over a 6-hour period. The final 20% of the total dose was given 24-hours post-HCA. Forty-eight hours later (72-hours post-HCA), the brain was harvested and analyzed for D6-Cy5 biodistribution. The dorsal hippocampus demonstrated the highest brain accumulation of D6-Cy5, which closely corresponds to the distribution of apoptotic neurons evident with histological staining and on confocal imaging. In injured brain regions, dendrimer traversed the BBB and localized within the target cells (injured neurons and microglia). This is the first known study to illustrate consistent neuronal/microglia uptake of a dendrimer-drug delivery system in a large animal model after systemic administration. These findings have exciting implications for the future development of novel therapeutics to mitigate neurocognitive deficits in this group of patients.